Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities

Sabeh, Malak El; Saha, Subbroto Kumar; Afrin, Sadia; Islam, Soriful; Borahay, Mostafa A.

doi:10.1007/s11010-021-04174-6

Cited by 22 publications

(19 citation statements)

References 224 publications

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Section: Leiomyoma (Uterine Fibroids)mentioning

confidence: 99%

“…WNT signaling has also been reported to mediate cellular processes in leiomyoma pathophysiology [ 197 , 206 , 207 , 208 ]. Several WNT ligands and other mediators have been overexpressed in leiomyoma to activate the WNT/CTNNB1 pathway to enhance leiomyoma progression [ 206 ]. Ono et al [ 207 ] have reported that estrogen and progesterone activate canonical WNT/CTNNB1 signaling to stimulate cellular proliferation in the leiomyoma side population of stem-like cells, but this is not seen in the myometrial cells.…”

Section: Leiomyoma (Uterine Fibroids)mentioning

confidence: 99%

“…The group also shows that WNT4 is overexpressed in CD34 + /CD49b − leiomyoma cells and can stimulate leiomyoma cell proliferation via WNT/CTNNB1 signaling and AKT [ 209 ]. Additionally, MED12 mutations have been implicated in the misregulation of WNT/CTNNB1 signaling, providing additional linage between two common mechanisms of leiomyoma development [ 206 , 210 , 211 , 212 ].…”

Section: Leiomyoma (Uterine Fibroids)mentioning

confidence: 99%

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Progesterone Actions and Resistance in Gynecological Disorders

MacLean

Hayashi

2022

Cells

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Estrogen and progesterone and their signaling mechanisms are tightly regulated to maintain a normal menstrual cycle and to support a successful pregnancy. The imbalance of estrogen and progesterone disrupts their complex regulatory mechanisms, leading to estrogen dominance and progesterone resistance. Gynecological diseases are heavily associated with dysregulated steroid hormones and can induce chronic pelvic pain, dysmenorrhea, dyspareunia, heavy bleeding, and infertility, which substantially impact the quality of women’s lives. Because the menstrual cycle repeatably occurs during reproductive ages with dynamic changes and remodeling of reproductive-related tissues, these alterations can accumulate and induce chronic and recurrent conditions. This review focuses on faulty progesterone signaling mechanisms and cellular responses to progesterone in endometriosis, adenomyosis, leiomyoma (uterine fibroids), polycystic ovary syndrome (PCOS), and endometrial hyperplasia. We also summarize the association with gene mutations and steroid hormone regulation in disease progression as well as current hormonal therapies and the clinical consequences of progesterone resistance.

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Section: Leiomyoma (Uterine Fibroids)mentioning

confidence: 99%

Section: Leiomyoma (Uterine Fibroids)mentioning

confidence: 99%

Section: Leiomyoma (Uterine Fibroids)mentioning

confidence: 99%

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Progesterone Actions and Resistance in Gynecological Disorders

MacLean

Hayashi

2022

Cells

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“…Los efectos antiproliferativos de la VitD sobre las células miometriales humanas y derivadas del leiomioma han sido documentados en estudios in vitro (46,47) . Esta inhibe tanto la Wnt4/β-catenina como la transducción de señales de la vía diana de rapamicina en células de mamífero, vías claves en la etiopatogénesis de los leiomiomas.…”

Section: Leiomiomas Uterinosunclassified

Deficiencia de vitamina D y patologías ginecológicas de la mujer en edad reproductiva

Mejia-Montilla

Reyna-Villasmil

2022

Rev peru ginecol obstet.

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La vitamina D está actualmente en el ámbito de la investigación en muchos campos de la medicina. Es conocido que tiene funciones fundamentales en el metabolismo del calcio y modelado óseo. La deficiencia de vitamina definida como la concentración de 25-hidroxicalciferol < 20 ng/mL es observada con frecuencia en pacientes con patologías ginecológicas. En las últimas dos décadas existe evidencia sobre la asociación de concentraciones séricas bajas de vitamina D con trastornos como diabetes mellitus y síndrome metabólico. Cada vez hay más informes que plantean el impacto del metabolismo de esta vitamina en el desarrollo de trastornos del sistema reproductor femenino. El receptor de vitamina D y la 1α-hidroxilasa están presentes en los órganos reproductivos, lo que sugiere que la vitamina D puede tener algún efecto en la modulación de las funciones celulares. Los efectos perjudiciales de la deficiencia han sido mostrados en pacientes con diagnóstico de síndrome de ovarios poliquísticos, endometriosis y leiomiomatosis. La suplementación de vitamina D debería agregarse a los esquemas de tratamiento de la mayoría de las patologías ginecológicas en pacientes con deficiencia, tanto por la mejora de la insulinorresistencia (como en las pacientes con síndrome de ovarios poliquísticos) como por los resultados del tratamiento de la infertilidad. El objetivo de esta revisión fue establecer los efectos de la deficiencia de vitamina D en patologías de la mujer en edad reproductiva.

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“…We also studied the top significant hypermethylated/ downregulated genes, selecting EFEMP1, FBLN2, ARHGAP10, and HTATIP2 because of their promising roles in UL. EFEMP1 is an extracellular matrix glycoprotein that suppresses the Wnt/β-catenin pathway in endometrial carcinoma [62]; is dysregulated in leiomyomas; and is one of the most important regulators of their pathophysiology [45,46,63]. Therefore, methylation and downregulation of EFEMP1 could enhance the Wnt/ β-catenin pathway and increase extracellular matrix formation in UL.…”

mentioning

confidence: 99%

Integrative analysis of the DNA methylome and transcriptome in uterine leiomyoma shows altered regulation of genes involved in metabolism, proliferation, extracellular matrix, and vesicles

Carbajo-García

Corachán

Juárez‐Barber

et al. 2022

The Journal of Pathology

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Uterine leiomyomas (ULs) are the most common benign tumors in women of reproductive age. Despite the high prevalence, tumor pathology remains unclear, which hampers the development of safe and effective treatments. Epigenetic mechanisms appear to be involved in UL development, particularly via DNA methylation that regulates gene expression. We aimed to determine the relationship between DNA methylation and gene expression in UL compared with adjacent myometrium (MM) to identify molecular mechanisms involved in UL formation that are under epigenetic control. Our results showed a different DNA methylation profile between UL and MM, leading to hypermethylation of UL, and a different global transcriptome profile. Integration of DNA methylation and whole‐transcriptome RNA‐sequencing data identified 93 genes regulated by methylation, with 22 hypomethylated/upregulated and 71 hypermethylated/downregulated. Functional enrichment analysis showed dysregulated biological processes and molecular functions involved in metabolism and cell physiology, response to extracellular signals, invasion, and proliferation, as well as pathways related to uterine biology and cancer. Cellular components such as cell membranes, vesicles, extracellular matrix, and cell junctions were dysregulated in UL. In addition, we found hypomethylation/upregulation of oncogenes (PRL, ATP8B4, CEMIP, ZPMS2‐AS1, RIMS2, TFAP2C) and hypermethylation/downregulation of tumor suppressor genes (EFEMP1, FBLN2, ARHGAP10, HTATIP2), which are related to proliferation, invasion, altered metabolism, deposition of extracellular matrix, and Wnt/β‐catenin pathway dysregulation. This confirms that key processes of UL development are under DNA methylation control. Finally, inhibition of DNA methyltransferases by 5‐aza‐2'‐deoxycitidine increased the expression of hypermethylated/downregulated genes in UL cells in vitro. In conclusion, gene regulation by DNA methylation is implicated in UL pathogenesis, and reversion of this methylation could offer a therapeutic option for UL. © 2022 The Pathological Society of Great Britain and Ireland.

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Wnt/β-catenin signaling pathway in uterine leiomyoma: role in tumor biology and targeting opportunities

Cited by 22 publications

References 224 publications

Progesterone Actions and Resistance in Gynecological Disorders

Progesterone Actions and Resistance in Gynecological Disorders

Deficiencia de vitamina D y patologías ginecológicas de la mujer en edad reproductiva

Integrative analysis of the DNA methylome and transcriptome in uterine leiomyoma shows altered regulation of genes involved in metabolism, proliferation, extracellular matrix, and vesicles

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